Many neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), lead to the irreversible destruction of neuronal axons. Once axons are destroyed, there is no mechanism left for neuronal signaling, thus a drastic reduction of brain capacity occurs. It is known that the degeneration of axons is an active process that is controlled by the neuron itself. In addition, it is known that if transport of proteins and organelles along axons is slowed, this process of axonal self-destruction is stimulated. Very little is known about the exact mechanisms that control axonal degeneration and its link to disrupted axon transport. However there are excellent markers of axon transport that can be used to characterize axon transport-associated degeneration. One of these markers is amyloid precursor protein (APP), which is found in axonal aggregates from neurodegeneration pathology specimens. This proposal seeks to design high-throughput screens that will find genetic modifiers of axon transport, and drug compound modifiers of APP-associated axonal degeneration. The long term goal of this work is thus to understand better the causes of axonal destruction in neurodegenerative diseases, and to find drugs that can slow or prevent axonal degeneration from occurring.